Modified carrier particles for use in dry powder inhalers

ABSTRACT

The invention relates to carrier particles for use in pharmaceutical compositions for the pulmonary administration of medicaments by means of dry powder inhalers. In particular, the invention relates to a novel technological process for obtaining a carrier modified so as to improve the efficiency of redispersion of active particles and hence increase the respirable fraction. After the treatment of the invention, the surface of said modified carrier particles can also be coated with a suitable additive so as to further improve the respirable fraction.

PRIOR ART

Inhalation anti-asthmatics are widely used in the treatment ofreversible airway obstruction, inflammation and hyperresponsiveness.

Presently, the most widely used systems for inhalation therapy are thepressurised metered dose inhalers (MDIs) which use a propellant to expeldroplets containing the pharmaceutical product to the respiratory tract.

However, despite their practicality and popularity, MDIs have somedisadvantages:

i), droplets leaving the actuator orifice could be large or have anextremely high velocity resulting in extensive oropharyngeal depositionto the detriment of the dose which penetrates into the lungs;

ii) the amount of drug which penetrates the bronchial tree may befurther reduced by poor inhalation technique, due to the commondifficulty of the patient to synchronise actuation form the device withinspiration

iii) chlorofluorocarbons (CFCs), such as freons contained as propellantsin MDIs, are disadvantageous on environmental grounds as they have aproven damaging effect on the atmospheric ozone layer.

Dry powder inhalers (DPIs) constitute a valid alternative to MDIs forthe administration of drugs to airways. The main advantages of DPIs are:

i) being breath-actuated delivery systems, they do not requireco-ordination of actuation since release of the drug is dependent on thepatient own inhalation;

ii) they do not contain propellants acting as environmental hazards;

iii) the velocity of the delivered particles is the same or lower thanthat of the flow of inspired air, so making them more prone to followthe air flow than the faster moving MDI particles, thereby reducingupper respiratory tract deposition.

DPIs can be divided into two basic types:

i) single dose inhalers, for the administration of pre-subdivided singledoses of the active compound;

ii) multidose dry powder inhalers (MDPIs), pre-loaded with quantities ofactive ingredient sufficient for multiple doses; each dose is created bya metering unit within the inhaler.

Drugs intended for inhalation as dry powders should be used in the formof micronised powder so they are characterized by particles of fewmicron particle size (μm). Said size is quantified by measuring acharacteristic equivalent sphere diameter, known as aerodynamicdiameter, which indicates the capability of the particles of beingtransported suspended in an air stream. Respirable particles aregenerally considered to be those with diameters from 0.5 to 6 μm, asthey are able of penetrating into the lower lungs, i.e. the bronchiolarand alveolar sites, where absorption takes place. Larger particles aremostly deposited in the oropharyngeal cavity so they cannot reach saidsites, whereas the smaller ones are exhaled.

Although micronisation of the active drug is essential for depositioninto the lower lungs during inhalation, it is also known that the finerthe particles, the stronger are the cohesion forces. Strong cohesionforces hinder the handling of the powder during the manufacturingprocess (pouring, filling). Moreover they reduce the flowability of theparticles while favoring the agglomeration and/or adhesion thereof tothe walls. In multidose DPI's, said phenomena impair the loading of thepowder from the reservoir to the aerosolization chamber, so giving riseto handling and metering accuracy problems.

Said drawbacks are also detrimental to the respirable fraction of thedelivered dose being the active particles unable to leave the inhalerand remaining adhered to the interior of the inhaler or leaving theinhaler as large agglomerates; agglomerated particles, in turn, cannotreach the bronchiolar and alveolar sites of the lungs. The uncertaintyas to the extent of agglomeration of the particles between eachactuation of the inhaler and also between inhalers and different batchesof particles, leads to poor dose reproducibility as well.

In an attempt to improve both the handling and the efficiency, the drypowders for inhalation are generally formulated by mixing the microniseddrug with a carrier material (generally lactose, preferably α-lactosemonohydrate) consisting of coarser particles. In such ordered mixtures,the micronised active particles, because of the electrostatic or Van derWaals interactions, mainly adhere to the surface of the carrierparticles whilst in the inhaler device; on the contrary, duringinhalation, a redispersion of the drug particles from the surface of thecarrier particles occurs allowing the formers to reach the absorptionsite into the lungs.

Nevertheless, the use of a carrier is not free of drawbacks in that thestrong interparticle forces between the two ingredients may prevent theseparation of the micronised drug particles from the surface of thecoarse carrier ones on inhalation, so compromising the availability ofthe drug to the respiratory tract. The surface of the carrier particlesis, indeed, not smooth but has asperities and clefts, which are highenergy sites on which the active particles are preferably attracted toand adhere more strongly; because of such strong, interparticle forces,they will be hardly leave the surface of the carrier particles and bedispersed in the respiratory tract.

Therefore the features of the carrier particles should be such as togive sufficient adhesion force to hold the active particles to thesurface of the carrier particles during manufacturing of the dry powderand in the delivery device before use, but that force of adhesion shouldbe low enough to allow the dispersion of the active particles in therespiratory tract.

The prior art discloses several approaches for manipulating theinterparticle interactions between the drug and the carrier in orderedpowder mixtures.

First, the carrier particles can be chosen according to their medianparticle size, taking into account the fact that a decrease in medianparticle size increases the adhesion force between drug and carrierparticles.

GB 1,242,211 and GB 1,381,872 disclose pharmaceutical powders for theinhalatory use in which the micronised drug (0.01-10 μm) is mixed withcarrier particles of sizes 30 to 80 μm and 80 to 150 μm, respectively;said mixtures can also contain a diluent of the same particle size asthe micronised drug.

The deaggregation of the active ingredient from the carrier duringinhalation can also be made more efficient by modifying the surfaceproperties of the carrier and/or by addition of a fine fraction (<10μm), preferably of the same material of the carrier (Podczeck F. AerosolSci. Technol. 1999, 31, 301-321; Lucas P. et al Resp. Drug Deliv. 1998,VI, 243-250).

GB 2,240,337 A discloses, for example, a controlled crystallizationprocess for the preparation of carrier particles with smoother surfaces,and, in particular, characterized by a rugosity of less than 1.75 asmeasured by air permeametry; in practice their smoothness is readilyapparent under electronic microscope examination. The use of saidcarrier particles allows to increase the respirable fraction of the drug(Kassem, Doctoral thesis of the London University, 1990).

EP 0,663,815 claims the use of carriers for controlling and optimizingthe amount of delivered drug during the aerosolisation phase, consistingof suitable mixtures of particles of size >20 μm and finer particles(<10 μm) Staniforth et al. (WO 95/11666) combine both the aforementionedteachings (i.e. modification of the surface properties of the carrierand addition of a fine fraction) by exploiting the effects of a millingprocess, preferably carried out in a ball mill, referred to as corrasion(corrasion is a term used in geology and it describes either the effectof the wind on rocks and the filling of valley with stones during theice age) Said process modifies the surface properties and it gets rid ofthe waviness of the carrier particles by dislodging any asperities inthe form of small grains without substantially changing the size of theparticles; the small grains, in turn, can be reattached to the surfacesof the particles either during the milling phase or after preventiveseparation followed by mixing, in order to saturate other high energysites such as clefts. Said preliminary handling of the carrier causesthe micronised drug particles to preferably link to the lower energysites, thus being subjected to weaker interparticle adhesion forces.

Podceck (J. Adhesion Sci. Technol. 1998, 12, 1323-1339), after havingstudied the influence of the corrasion process on the adhesion forces byblending the carrier with different percentages of fine particlefraction before addition of the drug, concluded however that suchprocess is not always sufficient to ensure effective redispersion butthe latter also depends on the initial surface roughness of the coarsecarrier particles.

Patent literature also suggests the use of powder formulations forinhalation wherein the adhesion between the carrier particles and theactive ingredient particles is further reduced by addition of suitableamounts of suitable additives.

In WO 96/23485, particles are mixed with an anti-adherent oranti-friction material consisting of one or more compounds selected fromamino acids (preferably leucine); phospholipids or surfactants; theamount of additive and the process of mixing are preferably chosen insuch a way as to not give rise to a real coating, but instead a partialcoating directed to the high energy sites. The carrier particles blendedwith the additive are preferably subjected to the corrasion process in aball mill as disclosed in WO 95/11666.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the particle size distribution after Malvern analysis ofthe carrier particles before and after pre-treatment in a mixer.

OBJECT OF THE INVENTION

It has now been found, and it is the object of the invention, that it ispossible to modify the surface properties of the carrier particles andsimultaneously modulate their interaction with the micronised drugparticles by producing in situ a fine fraction of the carrier itself,without submitting the coarse carrier particles to a milling process butby employing a conventional mixer.

The use of a mixer, which intrinsically assures milder conditions,allows to modify the surface properties of the carrier particles withoutsignificantly changing their sizes, crystalline structure andchemico-physical properties.

It has been indeed reported that the chemical compounds preferably usedas carrier, such as lactose, can undergo chemico-physical alterations,when subjected to mechanical stresses, such as milling (Otsuka et al. J.Pharm. Pharmacol. 43, 148-153,1991).

Moreover, hard treatments such as corrasion may moderately reduce thecristallinity of the additives used (Malcolmson R et al. RespiratoryDrug Deliv. 1998, VI, 365-367).

It has been also surprisingly found that, by virtue of the milderoperative conditions of the invention, the fraction of fine particles ofsize larger than 10 μm is poor, as proved by the particle size analysisvia laser diffractometry (Malvern). It is well known that only the finefraction below 10 μm, once redistributed onto the surface of the coarsecarrier particles, is indeed responsible for the decrease of theinterparticle forces, whereas the fine particles of size larger than 10μm, contribute to decrease the flowability of the powder. Further, theprocess of the invention yields a fraction of carrier particles whosevariation of the starting mean aerodynamic diameter is less than 20%.

On the contrary, milling, as reported above, is a hard process whichproduces a fine fraction with a much wider particle size distributionwhich, in turn, could be detrimental for the flow properties of themixture. Therefore, the powders made with carriers preventivelysubjected to milling processes could turn out to be not flowable enoughto be suitable for multidose inhalers. Accordingly, the carrierssubjected to the milling process often require a further separation stepin order to select the fine fraction suitable for being mixed with thecoarse carrier particles and discard that one which can be detrimentalto the flow properties of the powder.

By operating according to the process of the present invention, the flowproperties of the carrier are not significantly affected, as indicatedby the Carr index as well as by the Flodex test. The process of theinvention allows therefore to avoid the further separation step of thefine fraction suitable for being mixed with the coarse carrierparticles.

The mixing process of the invention, compared with the milling processas described in WO 95/11666, allows to remarkably reduce the time oftreatment. In a preferred embodiment of the invention, carriers withsuitable properties are indeed obtained after 30 minutes of treatment ina sigma blade mixer whereas, according to WO 95/11666, carrier particlesshould be milled for at least one hour and preferably six hours.

Finally, the process of the invention provides a carrier for dry powdersfor inhalation able of giving good performances in terms of respirablefraction of the drug as demonstrated by the examples reported.

Advantageously the carrier particles are treated in any mixer, of anysize and shape, equipped with a rotating element. Preferably the carrierparticles are treated in mixers constituted of a stationary or rotatingbody equipped with any rotatory element (blade, screw) or in the highenergy mixers (“high-shear”) and blended for a total time ranging from 5to 360 minutes.

Even more preferably the carrier particles are treated in a sigma-blademixer at a rate of 100-300 r.p.m and for 30 minutes.

The carrier particles may be constituted of any pharmacologicallyacceptable inert material or combination thereof; preferred carriers arethose made of crystalline sugars, in particular lactose; the mostpreferred are those made of α-lactose monohydrate. Advantageously thediameter of the carrier particles lies between 20 and 1000 μm,preferably between 90 and 150 μm.

A further aspect of the invention relates to the preparation of carrierpowders in which, after treatment in a mixer, the carrier particles aremixed with suitable amounts, preferably from 0.05 to 2% by weight, ofadditives able of further reducing the drug-carrier interparticleforces, thereby increasing the respirable fraction.

The additives can be selected from those belonging to the class of thelubricants, such as metal stearates or to the classes of anti-adherentagents or glidants.

The preferred lubricant is magnesium stearate, but stearic acid, sodiumstearyl fumarate and sodium benzoate can also be used.

A further aspect of the invention are the formulations for inhalationobtained by mixing the active ingredient particles (with a meanaerodynamic diameter of less than 5 μm with carrier powders obtainedaccording to the process of the invention.

The preferred active particles will be particles of one or mixture ofdrugs which are usually administered by inhalation for the treatment ofrespiratory diseases, for example steroids such as beclomethasonedipropionate, flunisolide and budesonide; β-agonists such as salbutamol,formoterol, salmeterol, terbutaline and corresponding salts;anticholinergics such as ipratropium bromide. Any other activeingredient suitable for pulmonary and/or nasal delivery can be anywayused in these formulations.

The process of the invention is illustrated by the following examples.

EXAMPLE 1 a) Preparation of the Carrier

α-Lactose monohydrate with a starting particle size between. 90 to 150μm is mixed for 30 minutes in a sigma blade mixer. At the end of thetreatment, only a slight reduction of the particle size is observed.

The Malvern analysis pattern referring to the particle size distributionof the carrier particles before (- -) and after (_) the pre-mixingtreatment is reported in FIG. 1 whereas the relevant data are reportedin Table 1.

TABLE 1 Particle size distribution (μm) Unmixed Pre-mixed Malvern d (v,0.1) 100.4  61.4 d (v, 0.5) 138.3 127.1 d (v, 0.9) 197.8 187.7

b) Preparation of the Beclomethasone Dipropionate (BDP)/Lactose BinaryMixture

The carrier powder obtained according to the process a) is mixed withsuch an amount of micronised beclomethasone dipropionate as to obtain aratio of 200 μm of active to 26 mg total mixture.

c) Characterization of the Mixture

The active ingredient/carrier mixture was characterized by its densityand flowability parameters.

The poured density (dv) and the tapped density (ds) were calculated asfollows. Powder mixtures (20 g) were poured into a glass graduatedcylinder and dv was calculated dividing the weight by the volume; ds wascalculated from the volume obtained after tapping the powder mixture 500times using a commercially available apparatus.

The flowability was evaluated from the Carr's index calculated accordingto the following formula:${{{Carr}'}s\quad {index}\quad (\%)} = {\frac{{ds} - {dv}}{ds} \times 100}$

A Carr index of less than 25 is usually considered indicative of goodflowability characteristics.

The flowability properties were also determined by using a Flodextester. The determination is based upon the ability of the powdermixture to fall freely through holes of different diameters placed atthe bottom of a cylinder. The powder was poured into the cylinder via apowder funnel. The flowability index is given in millimeter diameter ofthe smallest hole through which the powder falls freely.

d) Determination of the Aerosol Performances

An amount of powder for inhalation was loaded in a multidose inhaler(Pulvinal®—Chiesi Pharmaceutical SpA, Italy).

The evaluation of the aerosol performances was performed by using a TwinStage Impinger apparatus, TSI (Apparatus of type A for the aerodynamicevaluation of fine particles described in FU IX, 4° supplement 1996).The equipment consists of two different glass elements, mutuallyconnected to form two chambers capable of separating the powder forinhalation depending on its aerodynamic size; the chambers are referredto as higher (stage 1) and lower (stage 2) separation chambers,respectively. A rubber adaptor secures the connection with the inhalercontaining the powder. The apparatus is connected to a vacuum pump whichproduces an air flow through the separation chambers and the connectedinhaler. Upon actuation of the pump, the air flow carries the particlesof the powder mixture, causing them to deposit in the two chambersdepending on their aerodynamic diameter. When the air flow is 60 l/min,the aerodynamic diameter limit value, dae, for the deposition in thelower separation chamber is 6.4 μm. Particles with higher dae deposit inStage 1 and particles with lower dae in Stage 2. In both stages, aminimum volume of solvent is used (30 ml in Stage 2 and 7 ml in Stage 1)to prevent particles -from adhering to the walls of the apparatus and topromote the recovery thereof.

The determination of the aerosol performances of the mixture obtainedaccording to the preparation process b) was carried out with the TSIapplying an air flow rate of 60 l/min for 5 seconds.

After nebulization of each dose of the dry powder in the Twin StageImpinger, the apparatus was disassembled and the amounts of drugdeposited in the two separation chambers were recovered by washing witha solvent mixture, then diluted to a volume of 50 ml in two volumetricflasks, one for Stage 1 and one for Stage 2, respectively. The amountscollected in the two volumetric flasks were then determined byHigh-Performance Liquid Chromatography (HPLC). The following parameters,as mean and relative standard deviations (RSD) of the values obtainedfrom three inhalers, by actuating 5 shots from each inhaler, werecalculated: i) the fine particle dose (FPD) which is the amount of drugfound in stage 1 of TSI; ii) the emitted dose which is the amount ofdrug delivered from the device recovered in stage 1+stage 2; iii) thefine particle fraction (FPF) which is the percentage of the emittedreaching stage 2 of TSI.

The results in terms of technological parameters and aerosolperformances are reported in Table 2, in comparison with a similarpreparation obtained by mixing the active ingredient with α-lactosemonohydrate lactose 90-150 μm not pre-treated in the mixer (standardpreparation)

TABLE 2 Apparent Technological Parameters Density (g/mL) StandardPreparation Preparation of Example 1 Poured 0.71 0.75 Tapped 0.80 0.90Flodex text (φ 4 mm) 4 4 Flow rate through 67 46 φ 4 mm (g/min) CarrIndex (%) 11 17 TSI test Mean weight (mg) 22.8 (3.3)  25.6 (2.6) Emitteddose (μg) 184.0 (3.3)  165.8 (6.9)  FPD (μg) 31.0 (50.9) 37.4 (8.9) FPF(%) 16.9 (53.2)  22.7 (10.6)

The results show that the flowability properties of the carrier are notsignificantly affected even in the presence of a slight reduction of theparticle size.

The treatment of the carrier also causes a significant increase of thefine particle fraction (t Student=2.42, p<0.005)

EXAMPLE 2 Preparation of a Salbutamol Base/Lactose Binary Mixture

Analogously to what described in example 1, a mixture containingmicronised salbutamol base as active ingredient in a ratio of 200 μg to24 mg total mixture was prepared.

The poured and tapped densities and the flowability characteristics weredetermined as described in example 1. The dry powder for inhalation wasloaded in a Pulvinal® inhaler and the aerosol performances weredetermined as described in example 1.

The results are reported in Table 3 in comparison with a similarpreparation obtained by mixing the active ingredient with α-lactosemonohydrate lactose 90-150 μm not pre-treated in a mixer (standardpreparation)

TABLE 3 Apparent Technological Parameters Density (g/mL) StandardPreparation Preparation of Example 2 Poured 0.71 0.74 Tapped 0.78 0.83Flodex text (φ 4 mm) 4 4 Flow rate through 72 — φ 4mm (g/min) Carr Index(%) 9 11 TSI test Mean weight (mg) 22.2 (1.7)  25.2 (3.3)  Emitted dose(μg) 185.0 (2.6)  168.2 (4.7)  FPD (μg) 60.1 (11.6) 80.9 (14.6) FPF (%)32.2 (11.5) 47.9 (11.4)

Also in this case, the results show that the flowability properties ofthe carrier do not significantly change.

Analogously, a significant increase (t=9.17, p <0.001) of the fineparticle fraction is observed with the carrier prepared according to theprocess a) described in example 1.

EXAMPLE 3 Preparation of a BDP/Lactose/Magnesium Stearate TernaryMixture

The powder carrier was prepared according to Example 1 a) by mixingα-lactose monohydrate for 30 minutes in a sigma blade mixer. Afterwardslactose was mixed with 0.25% by weight of magnesium stearate in aTurbula mixer for two hours. Finally the dry powder for inhalation wasprepared by mixing an amount of micronised beclomethasone dipropionatecorresponding to a dose of 200 μg and the carrier (lactose+magnesiumstearate) for 30 minutes in a Turbula rotating mixer at 32 rpm.

The poured and tapped densities, the flowability characteristics as wellas the aerosol performances were determined as described in example 1.

The results are reported in Table 4 in comparison with a standardformulation obtained by mixing 200 μg of micronised BDP with a carrierpowder consisting of 99.75% by weight of α-lactose monohydrate 90-150 μgnot pre-treated in a mixer, and 0.25% by weight of magnesium stearate(standard preparation).

TABLE 4 Apparent Technological Parameters Density (g/mL) StandardPreparation Preparation of Example 3 Poured 0.76 0.83 Tapped 0.81 0.92Flodex text (φ 4 mm) 4 4 Flow rate through 56 42 φ 4 mm (g/min) CarrIndex (%) 6 10 TSI test Mean weight (mg) 24.5 (2.5)  27.9 (3.2) Emitteddose (μg) 188.9 (4.5)  199.8 (2.2)  FPD (μg) 48.0 (19.5) 68.9 (5.6) FPF(%) 25.3 (15.3) 34.5 (5.2)

The flowability properties of the carrier do not significantly changeeven in the presence of a ternary mixture and a significant increase(t=8.29, p <0.001) of the fine particle fraction is observed with thecarrier prepared according to the invention.

What is claimed is:
 1. A process for modifying the surface properties ofparticles for use as carrier particles for the pulmonary administrationof micronised drugs by means of dry powder inhalers, comprising the stepof subjecting said carrier particles alone to a treatment of a mixerequipped with a rotating element, said mixer operating at a rate of 100to 300 r.p.m. in order to produce in situ a fine fraction of saidcarrier particles having a mean aerodynamic diameter of less than 10 μmand a Carr's index of less than
 25. 2. The process according to claim 1,wherein said carrier particles have a starting diameter between 90 to150 μm and said fine fraction of said carrier particles has a meanaerodynamic diameter of less than 10 μm.
 3. The process according toclaim 1, wherein the mixer is selected from those with a stationary orrotating body equipped with a rotatory element.
 4. The process accordingto claim 1, wherein the mixer is a sigma blade mixer and the rate ofmixing is comprised between 100 and 300 r.p.m.
 5. The process accordingto claim 1, wherein the mixing time of said carrier particles rangesfrom 5 to 360 minutes.
 6. The process according to claim 1, wherein themixing time is 30 minutes.
 7. The process according to claim 1, whereinsaid carrier particles consist of one or more saccharides.
 8. Theprocess according to claim 1, wherein said carrier particles consist ofα-lactose monohydrate.
 9. A process according to claim 1, wherein aftersaid treatment a suitable amount of an additive selected from the groupconsisting of lubricants, anti-adherent agents and glidants is added tothe carrier.
 10. A process according to claim 9, in which the amount ofadditive ranges from 0.05 to 2%.
 11. A process according to claim 9,wherein said additive comprises a lubricant and is magnesium stearate,stearic acid, sodium stearyl fumarate or sodium benzoate.
 12. A processaccording to claim 1, wherein after said treatment one or more activeingredients, whose particles have a mean aerodynamic diameter of lessthan 5 μm, are added to the carrier.
 13. A process according to claim12, in which the active ingredient is a β-agonist selected fromsalbutamol, formoterol, salmeterol, terbutaline or salts thereof.
 14. Aprocess according to claim 12, in which the active ingredient is anantiinflammatory steroid selected from beclomethasone dipropionate,flunisolide, budesonide and the epimers thereof.
 15. A process accordingto claim 12 in which the active ingredient is selected from the groupconsisting of ipratropium bromide or oxytropium bromide.
 16. A processaccording to claim 10, wherein said additive comprises a lubricant andis magnesium stearate, stearic acid, sodium stearyl fumarate or sodiumbenzoate.
 17. The process according to claim 3, wherein said rotatingelement is a blade or screw.
 18. The process according to claim 3,wherein said mixer is a high-shear mixer.
 19. The process according toclaim 11, wherein said lubricant is magnesium stearate.
 20. The processaccording to claim 1, wherein said carrier particles have a startingdiameter of between 20 to 1,000 μm.
 21. The process according to claim16, wherein said lubricant is magnesium stearate.